Process for producing organic esters of nitrophenyl dichloroacetamido propane diols



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PROCESS FOR PRQDUCING ORGANIC ESTERS OF NITROPHENYL DICHLOROACETAMIDO PRO- PANE DIOLS William H. Edgerton, Huntington Woods, Mich., assignor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application March 28, 1955 Serial No. 497,433

12 Claims. (Cl. 260-404) This invention relates to a process for producing certain therapeutically valuable esters. More particularly, the present invention relates to a method for producing 3-O-acyl esters of 1-p-nitrophenyl-2-dichloroacetamidopropane-1,3-diol having the general formula,

Threo form States Patent From the following description it will be apparent to I those skilled in the art that the starting materials, intermediates and ester products of the invention exist in structural or diastereoisomeric as well as optical isomeric form. The present invention is concerned with compounds having the threo diastereoisomeric as distinguished from the erythro diastereoisomeric form. The groups on the two asymmetric carbon atoms of such threo diastereoisomers have the same relative spacial configuration or arrangement as the groups on the two asymmetric carbon atoms of pseudo ephedrine and threose.

Because of the difficulty in representing these structural differences in graphic formulae, the customary structural formulae will be used in both the specification and claims and a notation placed below or to the side of the formula to designate the particular structural and optical configuration of the compound. Where the notation threo form appears, as it does above, the formula is to be interpreted in its generic sense, that is, as representing the D-threo and L-threo isomers in separated form as well as the racemic mixture thereof. Such a formula does not merely represent the optical mixture. In the specific formulae the notation [+1 will be used to designate dextro optical rotation and the notation to designate levo optical rotation.

In accordance with the invention threo-l-p-nitrophenyl-Z-dichloroacetamido-3-acyloxypropane-1 01 compounds having the formula given above are produced by ring-nitrating a l-phenyl-1-acyloxy-2-dichloroacetamido- 3-OR-substituted propane of formula,

Threo form "ice 2 to produce a l-p-nitrophenyl-1-acyloxy-2-dich1oroacetamido-3-OR-substituted propane of formula,

rim-@483 oH-omoR Threo form lHNOa l O-Acyl NH-(i-CHOI: NO -JJH CH-OHaOR Three form (B) lMlld hydrosis II OH NH-C-CHCh l l NO -QOH-4JH-CH2OR Threo form where R and Acyl have the same significance as given above.

The nitration in accordance with the transformation designated as A in the above diagram can be carried out using a mixture of concentrated nitric and sulfuric acids; nitric acid; or fuming nitric acid. The temperature of the reaction mixture is preferably maintained below 0 C. but in practice higher temperatures up to 25 C. are satisfactory. Temperatures as low as 50 can be employed but there is no particular advantage in employing a temperature lower than 25 C.

The transformation designated as B in the above diagram involves selectively removing the 1-O-acyl group present in the l-p-nitrophenyl-1-acyloXy-2-dichloroacetamido-B-OR-propane, by hydrolysis. This is accomplished by treating the propane compound with an alkaline agent dissolved in a water-miscible organic solvent in the presence of water at a temperature between about 20 to +25 C., and preferably between 5 to +10 C. Among the many alkaline agents which can be used are the alkali metal hydroxides and alcoholates, the alkaline earth metal hydroxides and alcoholates, the alkali metal carbonates, and the alkali metal bicarbonates. Among the many suitable organic solvents for the reaction are lower aliphatic alcohols such as methanol, ethanol, isopropanol, isobutanol; lower aliphatic ketones such as acetone, methyl ethyl ketone; cyclic ethers such as dioxane; and secondary and tertiary aliphatic amides such as methyland dimethyl-formamide. The preferred method of carrying out the selective hydrolysis is to maintain the temperature in the neighborhood of 5 C. and to use substantially stoichiometric proportions of the alkaline agent and the l-p-nitrophenyl-l-acyloxy-Z-dichloroacetamido-3-OR-propane compound.

The invention .is illustrated by the following examples.

Example 1 (a) 3 grams of D-threo-l-phenyl-1-dichloroacetoxy-2- dichloroacetamido 3 palmitoyloxypropane are slowly added to 30 ml. of fuming nitric acid at a temperature of -20 C. The reaction mixture is allowed to warm to 5 C. and is quenched by pouring into a slurry of ice and ethyl acetate. The mixture is neutralized by the addition of solid sodium carbonate and the ethyl acetate layer is separated, dried and concentrated by evaporation. The residual syrup is purified by crystallization from aqueous ethanol; M. P. 71'' C., [oi] =--18 (4% in ethyl acetate). The product, D-(--)-threo-l p-nitrophenyl-l-dichloracetoxy-Z-dichloroaeet amido S-pah'nitoyloxypropane, has the formula,

D-( )-threo form (b) A solution of 6.7 g. of D-()-threo-1-p-nitrophenyll-dichloroacetoxy-Z-dichloroacetamido l 3 palmitoyloxypropane in 50 ml. of dimethyl-formamide is cooled to 5 C. and 10.1 ml. of 0.981 N sodium hydroxide is added dropwise with stirring. The mixture is quenched in 60 ml. of cold water. The crystalline product which separates, D-( -threo-1-p-nitrophenyl-Z-dichloracetamido: 3-palmitoyloxypropane-l-ol, is purified by Washing first with aqueous ethanol and then with iso-octane; M. P. 8889 C. This product has the formula,

OHCli NOQdn-drL-onm-ii-Gmm D-( )-threo form The starting material for 1(a) above can be prepared by reacting D-threo-1-phenyl-2-dichloroacetamido propane-l,3-diol with an equivalent amount of palmitoyl chloride in a tertiary amide solvent in the presence of pyridine to obtain D-threo-1-phenyl-2-dichloroacetamido- 3-palmitoyloxypropane-l-ol and reacting an anhydrous pyridine solution of the latter compound with an excess of dichloroacetyl chloride. The reaction product, D- threo-l-phenyl-l-dichloroacetoxy 2 dichloracetamido- 3-palmitoyl-oxyp1'opane, is recovered by filtration and purifiied by recrystallization from ethanol.

Example 2 (a) 4.2 grams of D-threo-l-phenyl-l acetoxy-2-dich-- loro-acetamido-3-palmitoyloxypropane are added portion wise to 35 ml. of fuming nitric acid at a temperature between about l5 to -20 C. After standing for five minutes, the mixture is allowed to warm to *5 C. and is quenched by pouring into a slurry of ice and ethyl acetate. The mixture is neutralized by the addition of solid sodium carbonate and the acetate layer is separated, dried and concentrated by evaporation. The residual syrup is washed with water and with petroleum ether and recrystallized from xylene; M. P. 73 C., [0 1 14.5 (2% in ethyl acetate). This product, D-(--)- threo-l-p-nitrophenyl-l-acetoxy 2 dichldroacetamido-Iipalmitoyloxypropane, has the formula,

D-( )-threo form I OH NH D )-threo form The starting material for 2(a) above can be prepared by reacting an anhydrous pyridine solution of D-threol-phenyl-2-dichloroacetamido-3-palmitoyloxypropane-l-ol I with an excess of acetic anhydride. The reaction product,

D-threo-l-phenyl l acetoxy 2 dichloroacetamido-B- palmitoyloxypropane, is recovered by filtration and purified by recrystallization from a mixture of ethanol and 2,2,4-trimethyl-pentane.

Example 3 (a) 3 grams of D-threo-l-phenyl-l-dichloroacetoxy-2- dichloroactamido-3-stearoyloxypropane are added slowly to 30 ml. of fuming nitric acid at a temperature of 20 C. When the reaction is complete, the reaction mixture is quenched by pouring into a slurry of ice and ethyl acetate. The mixture is neutralized with sodium carbonate and the acetate layer is separated, dried and concentrated by evaporation. The residue is purified by recrystallization from aqueous ethanol. The product,

D a threo-l-p-nitrophenyl 1 dichloroacetoxy 2- dichloroac'et amido-li-stearoyl-oxypropane, has the formula,

D-( )-tlireo form (b) A solution of 7 g. of D-()-threo1-p-nitrophenyll-dichloroacetoxy-Z-dichloroacetamido 3 stearoyloxypropane in ml. of dirnethyl formamide is cooled to 5 C. and 10 ml. of normal sodium hydroxide solution is added dropwise with stirring. The reaction mixture is quenched in ml. of ice water. The crystalline product which separates, D-(+)-threo-l-p-nitrophenyl-Z-dichloroacetamido-3stearoyloxypropane, is collected and purified by washing with aqueous ethanol. The product has the formula,

D-( )-tlireo form The starting material for 3(a) above can be prepared by successive stearoylation and dicholoracetylation of D-threo-l-phenyl-Z-dichloroacetamidopropane 1,3 die] in the same manner indicated for the preparation of the starting material of Example 1(a).

Example 4 (a) 4.2 grams of DL-threo-1-phenyl-2-dichloroacetamrdo-l,3-d1palmitoyloxypropane are added slowly to 30 ml. of fuming nitric acid at a temperature of 20 C.

The temperature of the reaction mixture is allowed to rise to 0 C., and the mixture is quenched in a slurry of ice and ethyl acetate and neutralized with sodium carbonate. The organic layer is separated, dried and concentrated in vacuo. The residual product is purified by recrystallization from aqueous alcohol. The product, DL- threo-l-p-nitrophenyl 2 dichloroacetamido 1,3 dipalmitoyloxypropane, has the formula,

015E211 CHCII DL-threo form DL-threo form The starting material for 4(a) above can be prepared by reacting DL-threo-1-phenyl-2-dichloroacetamido-propane-1,3-diol with at least two equivalents of palmitoyl chloride in benzene at elevated temperature. The reaction product is isolated by concentrating the reaction mixture in vacuo and recrystallizing the residual product from ethanol.

I claim:

1. Process for producing a compound of formula,

II (DH I?IH-00HC12 NOQ-QH-OH-OEWR Threo form which comprises ring-nitrating at a temperature below 0 C. a l-phenyl-1-acyloxy-2-dichloroacetamido-3-OR-substituted propane of formula,

l Q-OH on-omoa Threo form to produce a l-p-nitrophenyl-1-acyloXy-2-dichloroacetamido-3-OR-substituted propane of formula,

| NOz-GH 0114232012 Threo form prises reacting a l-phenyl-l-dichloroacetoxy-2-dichloroacetamido-pa1mitoyloxypropane of formula,

0:0 NH-C-CHCI:

Threo form with a nitrating agent at a temperature below 0 C. to produce a 1-p-nitrophenyl-1-dichloroacetoxy-2-dichloroacetamido-3-palmitoyloxypropane of formula,

one], o

Threo form and subjecting the latter compound to hydrolysis with an alkaline agent at a temperature below 25 C.

3. Process for producing threo-l-p-nitrophenyl-Z-di chloroacetamido-3-stearoyloXypropane-1-ol which comprises reacting a l-phenyl-1-dichloroacetoxy-Z-dichloroacetamido-3-stearoyloxypropane of formula,

CHO]:

Threo form with a nitrating agent at a temperature below 0 C. to produce a 1-p-nitrophenyl-l-dichloroacetoxy-2-dichloroacetamido-3-stearoyloxypropane of formula,

CHCl: 0

0:0 NH-C-CHCI:

Threo form and subjecting the latter compound to hydrolysis with an alkaline agent at a temperature below 25 C.

4. Process for producing a threo-l-p-nitrophenyl-Z-dichloroacetamido-3-acyloxypropane-l-ol compound of formula,

OH NH-iil-CHCI:

Three form which comprises subjecting a 1-p-nitrophenyll-acyloxy- 2-dichloroacetamido-3-OR-substituted propane of formula,

Three form to hydrolysis with an alkaline agent at a temperature below 25 C.; where Acyl is a member of the group consisting of aliphatic carboxylic acid acyl radcals contanng sisting of aliphatic carboxylic acid acyl radicals containing l to 18 carbon atoms and halogen substituted lower aliphatic carboxylic acid acyl radicals and R is a member of the group consisting of palmitoyl and stearoyl radicals.

5. Process for producing threo-Lp-nitrophenyl-Z-dichloroacetamido-3-palmitoyloxypropane-l-ol, which comprises subjecting l-p-nitrophenyl-l-dichloroacetoxy-Z-dichloroacetamido-3-palmitoyloxypropane to hydrolysis with an alkaline agent at a temperature below 25 C.

6. Process for producing threo-l-p-nitrophenyl-Z-dichloroacetamido-3-stearoyloxypropane-1-01, which comprises subjecting l-p-nitrophenyl-l-dichloroacetoxy-Z-dichloroacetamido-3-stearoyloxypropane to hydrolysis with an alkaline agent at a temperature below 25 C.

7. A co'rnpound having the formula,

0 O-Acyl NH-h-cnon where Y is a member of the class consisting of H and N0 Acyl is a member of the group consisting of aliphatic carboxylic acid acyl radicals containing 1 to 18 carbon atoms and halogen substituted lew er aliphatic c'a'rboxylic acid acyl radicals and R is a member of the grou consisting of palmitoyl and staroyl radicals.

8. A compound hailing tlie foi'mula,

where Acyl is a member of the rou consisting of aliphatic carboxylic acid aeyl radicals containing 1 to 18 carbon atoms and halogen substit'iited iower' aliphatic carboxylic acid acyl radicals and R is a member of the group consisting (if palmito'yl and stearoyl radicals.

9. A compound having the formula,

acetoxy-Z-dichloroacetamido-3 -p almitoyloxypropane.

12. DL threo 1 p n'it'r'oplienyl 2 dichloroacetamido-1,3-dipalmitoyloxypropane.

References Cited in the file of this patent UNITED STATES PATENTS 2,483,884 Crooks er a1. Oct. 4, 1949 2,514,376 Crooks et a1 July 11, 1950 2,662,906 Edgefton' Dec. 15, 1953 

1. PROCESS FOR PRODUCING A COMPOUND OF FORMULA,
 7. A COMPOUND HAVING THE FORMULA, 